RNA-seq based mapping strategies to uncover heterogeneity in survival among Pancreatic Ductal Adenocarcinoma (PDAC) patients

2018 ◽  
Author(s):  
Archana Bhardwaj ◽  
Claire Josse ◽  
Daniel Van Daele ◽  
Marcela Chavez ◽  
Kristel Van Steen
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Rna Seq

Morphological classification of pancreatic ductal adenocarcinoma that predicts molecular subtypes and correlates with clinical outcome

Gut ◽  
2019 ◽  
Vol 69 (2) ◽  
pp. 317-328 ◽  
Author(s):  
Sangeetha N Kalimuthu ◽  
Gavin W Wilson ◽  
Robert C Grant ◽  
Matthew Seto ◽  
Grainne O’Kane ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Subtypes ◽  
Differentially Expressed Gene ◽  
Biological Significance ◽  
Treatment Strategies ◽  
Ductal Adenocarcinoma ◽  
Rna Seq ◽  
Gene Signatures ◽  
Significant Difference ◽  
Morphological Patterns

IntroductionTranscriptional analyses have identified several distinct molecular subtypes in pancreatic ductal adenocarcinoma (PDAC) that have prognostic and potential therapeutic significance. However, to date, an indepth, clinicomorphological correlation of these molecular subtypes has not been performed. We sought to identify specific morphological patterns to compare with known molecular subtypes, interrogate their biological significance, and furthermore reappraise the current grading system in PDAC.DesignWe first assessed 86 primary, chemotherapy-naive PDAC resection specimens with matched RNA-Seq data for specific, reproducible morphological patterns. Differential expression was applied to the gene expression data using the morphological features. We next compared the differentially expressed gene signatures with previously published molecular subtypes. Overall survival (OS) was correlated with the morphological and molecular subtypes.ResultsWe identified four morphological patterns that segregated into two components (‘gland forming’ and ‘non-gland forming’) based on the presence/absence of well-formed glands. A morphological cut-off (≥40% ‘non-gland forming’) was established using RNA-Seq data, which identified two groups (A and B) with gene signatures that correlated with known molecular subtypes. There was a significant difference in OS between the groups. The morphological groups remained significantly prognostic within cancers that were moderately differentiated and classified as ‘classical’ using RNA-Seq.ConclusionOur study has demonstrated that PDACs can be morphologically classified into distinct and biologically relevant categories which predict known molecular subtypes. These results provide the basis for an improved taxonomy of PDAC, which may lend itself to future treatment strategies and the development of deep learning models.

scholarly journals Author Correction: Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma

Cell Research ◽  
2019 ◽  
Vol 29 (9) ◽  
pp. 777-777
Author(s):  
Junya Peng ◽  
Bao-Fa Sun ◽  
Chuan-Yuan Chen ◽  
Jia-Yi Zhou ◽  
Yu-Sheng Chen ◽  
...  
Keyword(s):  
Single Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Malignant Progression ◽  
Ductal Adenocarcinoma ◽  
Rna Seq

Oncogenic roles of CEACAM6 in pancreatic ductal adenocarcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16744-e16744
Author(s):  
Daruka Mahadevan ◽  
Ritu Pandey ◽  
Yuliang Chen ◽  
Jacob Essif ◽  
Aisha Al-Khinji
Keyword(s):  
Gene Expression ◽  
Cell Adhesion ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Lines ◽  
Ductal Adenocarcinoma ◽  
Tumor Growth Inhibition ◽  
Rna Seq ◽  
Microarray Expression Data ◽  
Cellular Apoptosis ◽  
Anti Tumor Activity

e16744 Background: Carcinoembryonic cell adhesion molecule 6 (CEACAM6) is a cell adhesion receptor of the Ig-superfamily overexpressed in human Pancreatic Ductal Adenocarcinoma (PDA), enriching to the classical activated stroma subtype. CEACAM6 has multifaceted roles in PDA and is a poor prognostic maker (Pandey et al. Sci Rep 2019). We report functional correlative studies across PDA cell lines with high vs KO vs low of CEACAM6 and a PDX model with a therapeutic Mab. Methods: RNA-Seq and microarray expression data of PDA cell lines were downloaded from GEO using R (4.3), normalized and log transformed for analysis: CEACAM6 high vs. low were assessed for differential gene expression changes. Correlation of CEACAM6 levels with genes of interest was studied and compared with the CEACAM6 KO proteomic profile of HPAF-II cells. CEACAM6 WT vs. KO cells were profiled for protein kinase (PK) activity (PAMChip) and gene expression changes by RNA-Seq. NSG-CD34+ mice bearing PDX were evaluated with a humanized anti-CEACAM6 Mab for anti-tumor activity. Results: Differential expression analyses between PDA cell lines with low vs KO vs high CEACAM6 resulted in identifying similar markers changing in quantitative proteomics. KRT20, SYTL1, SKIL, CES1P1, MAN1A1 were down-regulated and HMOX1, CPNE2, ABCD1 were up-regulated in CEACAM6 low or KO cell lines. Specific PKs are upregulated in CEACAM6 KO enriching to the TK family (EPH A1, 3, 4, 8 and HCK), AGC family (e.g. AKT, PKA) and cellular apoptosis (e.g. BAD). RNA-Seq of CEACAM6 WT vs KO cells reconfirmed the up-regulation of MMP1, IL2RG, ATP6V0D2 and low expression of KRT20, AGK and MAN1A1 in CEACAM6 KO cells. Pharmacologic inhibition with a humanized anti-CEACAM6 scFv-Fc (IgG4) in PDA PDX of NSG CD34+ mice demonstrated ~55% tumor growth inhibition (TGI) with enhanced survival of > 14 days vs. control. Conclusions: CEACAM6 is expressed exclusively in primates and humans and plays multifaceted oncogenic roles in PDA pathogenesis. When CEACAM6 is disrupted, ECM proteins are altered reshaping the stroma, activating specific PKs and priming apoptosis. The therapeutic anti-CEACAM6 Mab possesses anti-tumor activity with associated cellular apoptosis and increased mouse survival.

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